The p53 tumor suppressor gene is one of the most important genes in human cancer. Unlike the overwhelming majority of oncogenes and tumor suppressor genes, the TP53 gene is distinguished by the presence of single nucleotide polymorphisms in the coding region, some of which alter p53 function. Several years ago we reported that a polymorphism at amino acid 47 (Pro47Ser, rs1800371) of TP53 occurs in 1:40 African Americans and up to 1:10 of Africans. We showed that this polymorphism markedly impairs the phosphorylation of p53 on a critical residue, serine 46, and also significantly impairs the apoptotic ability of p53. In order to assess the impact of this polymorphism on cancer risk and therapy, we created a mouse model for the S47 variant, and compared it to wild type human p53. We also analyzed human lymphoblast cell lines that are homozygous for the S47 variant, compared to WT p53. We find in both mouse and human cells that the S47 variant has markedly decreased ability to induce apoptosis in response to genotoxic agents, particularly cisplatin. S47 also has decreased ability to transactivate a small subset of p53 target genes involved in apoptosis and metabolism (NOXA, GLS2 and SCO2). We show that cells with S47 have dramatic resistance to some chemotherapeutic agents, yet intriguingly, show increased sensitivity to at least one other agent. We show that S47 mice are susceptible to a wide variety of spontaneous cancers. Finally, we show that the S47 allele is a significant risk factor for breas cancer in pre-menopausal African American women (OR 1.84, p=0.03). The broad, long term objective of this proposal is to better define the mechanisms for impaired tumor suppression by S47. An added goal is to identify the impact of S47 on the response to therapy in a mouse model of breast cancer. There are three aims. In Aim 1, we will test the ability of S47 to suppress cancer when it exists as a single allele in mice (S47/ - and S47/WT). In Aim 2 we will assess the impact of the S47 allele on breast cancer incidence and p53 function in our novel animal model. We will also assess the efficacy of chemotherapeutic agents commonly used for breast cancer. In Aim 3 we will focus on p53 target genes with impaired transactivation by S47, and test their contribution tumor suppression. We will also elucidate the mechanism for impaired transcription by S47, with focus on iASPP, a protein with increased ability to interact with S47. We believe these studies will probe deeply the mechanism for impaired tumor suppression, and the consequences of S47 on cancer risk and efficacy of therapy. For these studies we include experts in p53 and gene expression (Murphy), mouse models of breast cancer (Huang), metabolism (Raychaudhuri), and biostatistics (Liu). The proposed research marks the first time that the impact of this deleterious polymorphism on breast cancer risk and therapy will be assessed.